In silico study of inhibitory capacity of sacubitril/valsartan toward neprilysin and angiotensin receptor.

Heart failure (HF) is a life-threatening condition that occurs when the heart cannot pump enough blood and oxygen to meet the body's needs. It affects mostly the elderly, commonly from the male population, especially those with obesity, diabetes, or some other chronic condition. It can be treated with different medications, and promising results were shown by a relatively new medicament called Entresto. Results obtained from molecular docking and molecular dynamics simulations to examine the inhibitory capacity of Entresto are presented in this study. Parameters obtained by the molecular docking simulations show that both parts of Entresto (sacubitril (SAC) and valsartan (VAL)) interact with targeted proteins, and inhibit their physiological function. Simulations of molecular dynamics revealed some interesting inhibitory patterns. SAC was discovered to produce structural alterations in neprilysin by binding to it, reducing neprilysin's physiological activity. In addition to blocking the active site, SAC binding causes the enzyme's structure to become less compact over time, causing changes in its biochemical characteristics and preventing the enzyme from performing its biological function. Similar to SAC, VAL also causes deviations in the structure of angiotensin receptors. The angiotensin receptor GPCR (G-protein-coupled receptors) is immersed in the lipid bilayer, and changes in the tertiary structure are only visible through RMSD and RMSF, not by examining R g. In this regard, MD simulations validated the results of molecular docking simulations, demonstrating that both SAC and VAL had inhibitory potential towards the neprilysin and angiotensin receptors, respectively.

Virtual ABI: A computationally derived ABI index for noninvasive assessment of femoro-popliteal bypass surgery outcome.

BACKGROUND AND OBJECTIVE: Peripheral arterial disease of the lower limbs, which affects 12-14% of the population, is often treated by bypassing a blocked portion of the vessel. Due to the limited ability of clinicians to predict the outcome of a selected bypass strategy, the five-year graft occlusion ranges from 50% to 90%, with a 20% risk of amputation in the first 5 years after the surgery. The aim of this study was to develop a computational procedure that could enable surgeons to reduce negative effects by assessing patient-specific response to the available surgical strategies. METHODS: The Virtual ABI assumes patient-specific finite element modeling of patients' hemodynamics from routinely acquired medical scans of lower limbs. The key contribution of this study is a novel approach for prescribing boundary conditions, which combines noninvasive preoperative measurements and results of numerical simulations. RESULTS: The validation performed on six follow-up cases indicated high reliability of the Virtual ABI, since the correlation with the experimentally measured values of ankle-brachial index was R² = 0.9485. CONCLUSION: The initial validation showed that the proposed Virtual ABI is a noninvasive procedure that could assist clinicians to find an optimal strategy for treating a particular patient by varying bypass length, choosing adequate diameter, position and shape.

Synthesis and Biological Screening of New 4-Hydroxycoumarin Derivatives and Their Palladium(II) Complexes.

Two newly synthesized 4-hydroxycoumarin bidentate ligands (L1 and L2) and their palladium(II) complexes (C1 and C2) were screened for their biological activities, in vitro and in vivo. Structures of new compounds were established based on elemental analysis, 1H NMR, 13C NMR, and IR spectroscopic techniques. The obtained compounds were tested for their antioxidative and cytotoxic activities and results pointed to selective antiradical activity of palladium(II) complexes towards •OH and -•OOH radicals and anti-ABTS (2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) cation radical) activity comparable to that of ascorbate. Results indicated the effect of C1 and C2 on the enzymatic activity of the antioxidative defense system. In vitro cytotoxicity assay performed on different carcinoma cell lines (HCT166, A375, and MIA PaCa-2), and one healthy fibroblast cell line (MRC-5) showed a cytotoxic effect of both C1 and C2, expressed as a decrease in carcinoma cells' viability, mostly by induction of apoptosis. In vivo toxicity tests performed on zebrafish embryos indicated different effects of C1 and C2, ranging from adverse developmental effect to no toxicity, depending on tested concentration. According to docking studies, both complexes (C1 and C2) showed better inhibitory activity in comparison to other palladium(II) complexes.

AI in Medical Imaging Informatics: Current Challenges and Future Directions.

This paper reviews state-of-the-art research solutions across the spectrum of medical imaging informatics, discusses clinical translation, and provides future directions for advancing clinical practice. More specifically, it summarizes advances in medical imaging acquisition technologies for different modalities, highlighting the necessity for efficient medical data management strategies in the context of AI in big healthcare data analytics. It then provides a synopsis of contemporary and emerging algorithmic methods for disease classification and organ/ tissue segmentation, focusing on AI and deep learning architectures that have already become the de facto approach. The clinical benefits of in-silico modelling advances linked with evolving 3D reconstruction and visualization applications are further documented. Concluding, integrative analytics approaches driven by associate research branches highlighted in this study promise to revolutionize imaging informatics as known today across the healthcare continuum for both radiology and digital pathology applications. The latter, is projected to enable informed, more accurate diagnosis, timely prognosis, and effective treatment planning, underpinning precision medicine.

Spectroscopic and theoretical investigation of the potential anti-tumor and anti-microbial agent, 3-(1-((2-hydroxyphenyl)amino)ethylidene)chroman-2,4-dione.

The coumarin-orthoaminophenol derivative was prepared under mild conditions. Based on crystallographic structure, IR and Raman, 1H and 13C NMR spectra the most applicable theoretical method was determined to be B3LYP-D3BJ. The stability and reactivity parameters were calculated, in the framework of NBO, QTAIM and Fukui functions, form the optimized structure. This reactivity was then probed in biological systems. The antimicrobial activity towards four bacteria and three fungi species was examined and activity was proven. In vitro cytotoxic effects, against human epithelial colorectal carcinoma HCT-116 and human healthy lung MRC-5 cell lines, of the investigated substance are also tested. Compound showed significant cytotoxic effects on HCT-116 cells, while on MRC-5 cells showed no cytotoxic effects. The effect of hydroxy group in ortho-position on the overall reactivity of molecule was examined through molecular docking with Glutathione-S-transferases.

Assessment of cortical bone fracture resistance curves by fusing artificial neural networks and linear regression.

Bone injures (BI) represents one of the major health problems, together with cancer and cardiovascular diseases. Assessment of the risks associated with BI is nontrivial since fragility of human cortical bone is varying with age. Due to restrictions for performing experiments on humans, only a limited number of fracture resistance curves (R-curves) for particular ages have been reported in the literature. This study proposes a novel decision support system for the assessment of bone fracture resistance by fusing various artificial intelligence algorithms. The aim was to estimate the R-curve slope, toughness threshold and stress intensity factor using the two input parameters commonly available during a routine clinical examination: patients age and crack length. Using the data from the literature, the evolutionary assembled Artificial Neural Network was developed and used for the derivation of Linear regression (LR) models of R-curves for arbitrary age. Finally, by using the patient (age)-specific LR models and diagnosed crack size one could estimate the risk of bone fracture under given physiological conditions. Compared to the literature, we demonstrated improved performances for estimating nonlinear changes of R-curve slope (R2 = 0.82 vs. R2 = 0.76) and Toughness threshold with ageing (R2 = 0.73 vs. R2 = 0.66).

Acceleration of Image Segmentation Algorithm for (Breast) Mammogram Images Using High-Performance Reconfigurable Dataflow Computers.

Image segmentation is one of the most common procedures in medical imaging applications. It is also a very important task in breast cancer detection. Breast cancer detection procedure based on mammography can be divided into several stages. The first stage is the extraction of the region of interest from a breast image, followed by the identification of suspicious mass regions, their classification, and comparison with the existing image database. It is often the case that already existing image databases have large sets of data whose processing requires a lot of time, and thus the acceleration of each of the processing stages in breast cancer detection is a very important issue. In this paper, the implementation of the already existing algorithm for region-of-interest based image segmentation for mammogram images on High-Performance Reconfigurable Dataflow Computers (HPRDCs) is proposed. As a dataflow engine (DFE) of such HPRDC, Maxeler's acceleration card is used. The experiments for examining the acceleration of that algorithm on the Reconfigurable Dataflow Computers (RDCs) are performed with two types of mammogram images with different resolutions. There were, also, several DFE configurations and each of them gave a different acceleration value of algorithm execution. Those acceleration values are presented and experimental results showed good acceleration.

Real-time monitoring of cytotoxic effects of electroporation on breast and colon cancer cell lines.

PURPOSE: To study the effects of electroporation on different cell lines. MATERIAL: The effects of electroporation on human breast cancer (MDA-MB-231), human colon cancer (SW-480 and HCT-116), human fibroblast cell line (MRC-5), primary human aortic smooth muscle cells (hAoSMC) and human umbilical vein endothelial cells (HUVEC) were studied. Real-time technology was used for cell viability monitoring. Acridine orange/ethidium bromide assay was applied for cell death type determination. A numerical model of electroporation has been proposed. RESULTS: Electroporation induced inhibition of cell viability on dose (voltage) dependent way. The electroporation treatment 375-437.5Vcm-1 caused irreversible electroporation of cancer cells and reversible electroporation of healthy cells. The application of lower voltage rating (250Vcm-1) led to apoptosis as the predominant type of cell death, whereas the use of higher voltage (500Vcm-1) mainly caused necrosis. CONCLUSION: Electroporation represents a promising method in cancer treatment. Different cancer cell lines had different response to the identical electroporation treatment. Electroporation 375-437.5Vcm-1 selectively caused permanent damage of cancer cells (SW-480), while healthy cells (MRC-5, hAoSM and HUVEC) recovered after 72h. The type of cell death is dependent of electroporation conditions. The proposed numerical model is useful for the analysis of phenomena related to electroporation treatment.

Finite element analysis of uncommonly large renal arteriovenous malformation--adjacent renal cyst complex.

BACKGROUND: Renal arteriovenous malformation (RAVM) represents abnormal communication between the intrarenal arterial and venous system. The purpose of this study was to investigate hemodynamics and biomechanics quantities which may influence the instability of RAVM and imply clinical complications. METHODS: A detailed 3D reconstruction of RAVM was obtained from the patient CT scans, aortic inlet flow was measured by color-flow Doppler ultrasound, while material characteristics were adopted from the literature. A numerical finite element analysis (FEA) of the blood flow was performed by solving the governing equations for the viscous incompressible flow. The physical quantities calculated at the systolic and diastolic peak moment were velocity, pressure, shear stress and drag forces. RESULTS: We reported a case of a 50-year-old patient with a large RAVM and adjacent renal cyst, who unsuccessfully underwent two attempts of embolization that resulted in the consequent nephrectomy. FEA showed that the cyst had a very low pressure intensity and velocity field (with unstable flow in diastolic peak). For both systolic and diastolic moments, increased values of wall shear stress were found on the places with intensive wall calcification. Unusually high values of drag force which would likely explain the presence of pressure in the cystic formation were found on the infero-medial side where the cyst wall was the thinnest and where the flow streamlines converged. CONCLUSIONS: FEA showed that the hemodynamics of the cyst-RAVM complex was unstable making it prone to rupture. Clinically established diagnosis of imminent rupture together with unfavorable hemodynamics of the lesion consequently made additional attempts of embolization risky and unsuccessful leading to total nephrectomy.

Numerical and experimental analysis of factors leading to suture dehiscence after Billroth II gastric resection.

The main goal of this study was to numerically quantify risk of duodenal stump blowout after Billroth II (BII) gastric resection. Our hypothesis was that the geometry of the reconstructed tract after BII resection is one of the key factors that can lead to duodenal dehiscence. We used computational fluid dynamics (CFD) with finite element (FE) simulations of various models of BII reconstructed gastrointestinal (GI) tract, as well as non-perfused, ex vivo, porcine experimental models. As main geometrical parameters for FE postoperative models we have used duodenal stump length and inclination between gastric remnant and duodenal stump. Virtual gastric resection was performed on each of 3D FE models based on multislice Computer Tomography (CT) DICOM. According to our computer simulation the difference between maximal duodenal stump pressures for models with most and least preferable geometry of reconstructed GI tract is about 30%. We compared the resulting postoperative duodenal pressure from computer simulations with duodenal stump dehiscence pressure from the experiment. Pressure at duodenal stump after BII resection obtained by computer simulation is 4-5 times lower than the dehiscence pressure according to our experiment on isolated bowel segment. Our conclusion is that if the surgery is performed technically correct, geometry variations of the reconstructed GI tract by themselves are not sufficient to cause duodenal stump blowout. Pressure that develops in the duodenal stump after BII resection using omega loop, only in the conjunction with other risk factors can cause duodenal dehiscence. Increased duodenal pressure after BII resection is risk factor. Hence we recommend the routine use of Roux en Y anastomosis as a safer solution in terms of resulting intraluminal pressure. However, if the surgeon decides to perform BII reconstruction, results obtained with this methodology can be valuable.

Computer methods for follow-up study of hemodynamic and disease progression in the stented coronary artery by fusing IVUS and X-ray angiography.

Despite a lot of progress in the fields of medical imaging and modeling, problem of estimating the risk of in-stent restenosis and monitoring the progress of the therapy following stenting still remains. The principal aim of this paper was to propose architecture and implementation details of state of the art of computer methods for a follow-up study of disease progression in coronary arteries stented with bare-metal stents. The 3D reconstruction of coronary arteries was performed by fusing X-ray angiography and intravascular ultrasound (IVUS) as the most dominant modalities in interventional cardiology. The finite element simulation of plaque progression was performed by coupling the flow equations with the reaction-diffusion equation applying realistic boundary conditions at the wall. The alignment of baseline and follow-up data was performed automatically by temporal alignment of IVUS electrocardiogram-gated frames. The assessment was performed using three six-month follow-ups of right coronary artery. Simulation results were compared with the ground truth data measured by clinicians. In all three data sets, simulation results indicated the right places as critical. With the obtained difference of 5.89 ± ~4.5% between the clinical measurements and the results of computer simulations, we showed that presented framework is suitable for tracking the progress of coronary disease, especially for comparing face-to-face results and data of the same artery from distinct time periods.

Mining data from hemodynamic simulations for generating prediction and explanation models.

One of the most common causes of human death is stroke, which can be caused by carotid bifurcation stenosis. In our work, we aim at proposing a prototype of a medical expert system that could significantly aid medical experts to detect hemodynamic abnormalities (increased artery wall shear stress). Based on the acquired simulated data, we apply several methodologies for1) predicting magnitudes and locations of maximum wall shear stress in the artery, 2) estimating reliability of computed predictions, and 3) providing user-friendly explanation of the model's decision. The obtained results indicate that the evaluated methodologies can provide a useful tool for the given problem domain.

Transient finite element modeling of functional electrical stimulation.

Transcutaneous functional electrical stimulation is commonly used for strengthening muscle. However, transient effects during stimulation are not yet well explored. The effect of an amplitude change of the stimulation can be described by static model, but there is no differency for different pulse duration. The aim of this study is to present the finite element (FE) model of a transient electrical stimulation on the forearm. Discrete FE equations were derived by using a standard Galerkin procedure. Different tissue conductive and dielectric properties are fitted using least square method and trial and error analysis from experimental measurement. This study showed that FE modeling of electrical stimulation can give the spatial-temporal distribution of applied current in the forearm. Three different cases were modeled with the same geometry but with different input of the current pulse, in order to fit the tissue properties by using transient FE analysis. All three cases were compared with experimental measurements of intramuscular voltage on one volunteer.

Comparative spectroscopic and mechanistic study of chelation properties of fisetin with iron in aqueous buffered solutions. Implications on in vitro antioxidant activity.

Fisetin (3,3',4',7-tetrahydroxyflavone) has been investigated for its ability to bind iron in a wide range of pH values of acetate and phosphate buffered solutions. To assess the relevant interactions of iron with fisetin, combined spectroscopic (UV/visible, Raman, MS) and theoretical approaches were used. The chelation sites, stoichiometry, stability and the dependence of the complexes structures on pH were defined. The results pointed to the formation of two iron-fisetin complexes with stoichiometries of 1 : 1 and 1 : 2, depending on the pH. Results of vibrational analysis and theoretical calculations implicated the 3-hydroxyl-4-carbonyl group as a chelating site in acidic media while catechol (3'-hydroxyl-4'-hydroxyl) group was identified as the chelating group in neutral and alkaline media. Determined relative, conditional, stability constants with iron-fisetin were in the range from 6 × 10(4) dm(3) mol(-1) to 7 × 10(9) dm(6) mol(-2). Competition experiments demonstrated that fisetin bound iron less strongly than EDTA and citric acid under the investigated experimental conditions. Rate constant values calculated for the fast step of the DPPH reduction for fisetin and the iron-fisetin complex are k(1) = 225.75 dm(3) mol(-1) s(-1) and k(1) = 658.00 dm(3) mol(-1) s(-1). These values fit within the interval of the rate constant values which are typical for antioxidants which have a single polyphenolic nucleus. The equilibrium geometries, optimized at the B3LYP/6-311 + G(d,p) and M06/6-311 + G(d,p) levels of theory, predicted structural modifications between the ligand molecule in the free state and in the complex structure. The theoretical model has been validated by both vibrational and electronic spectroscopies.